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Nucleic Acids Res. Oct 25, 1995; 23(20): 4202–4209.
PMCID: PMC307363

CGG repeats associated with DNA instability and chromosome fragility form structures that block DNA synthesis in vitro.


A large increase in the length of a CGG tandem array is associated with a number of triplet expansion diseases, including fragile X syndrome, the most common cause of heritable mental retardation in humans. Expansion results in the appearance of a fragile site on the X chromosome in the region of the CGG array. We show here that CGG repeats readily form a series of barriers to DNA synthesis in vitro. There barriers form only when the (CGG)n strand is used as the template, are K(+)-dependent, template concentration-independent, and involve hydrogen bonding between guanines. Chemical modification experiments suggest these blocks to DNA synthesis result from the formation of a series of intrastrand tetraplexes. A number of lines of evidence suggest that both triplet expansion and chromosome fragility are the result of replication defects. Our data are discussed in the light of such evidence.

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  • Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG, Jr, Warren ST, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991 Dec 20;67(6):1047–1058. [PubMed]
  • Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science. 1991 Jun 21;252(5013):1711–1714. [PubMed]
  • Knight SJ, Voelckel MA, Hirst MC, Flannery AV, Moncla A, Davies KE. Triplet repeat expansion at the FRAXE locus and X-linked mild mental handicap. Am J Hum Genet. 1994 Jul;55(1):81–86. [PMC free article] [PubMed]
  • Hirst MC, Barnicoat A, Flynn G, Wang Q, Daker M, Buckle VJ, Davies KE, Bobrow M. The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE. Hum Mol Genet. 1993 Feb;2(2):197–200. [PubMed]
  • Snow K, Tester DJ, Kruckeberg KE, Schaid DJ, Thibodeau SN. Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation. Hum Mol Genet. 1994 Sep;3(9):1543–1551. [PubMed]
  • Glover TW, Stein CK. Chromosome breakage and recombination at fragile sites. Am J Hum Genet. 1988 Sep;43(3):265–273. [PMC free article] [PubMed]
  • Nancarrow JK, Kremer E, Holman K, Eyre H, Doggett NA, Le Paslier D, Callen DF, Sutherland GR, Richards RI. Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis. Science. 1994 Jun 24;264(5167):1938–1941. [PubMed]
  • Kunst CB, Warren ST. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell. 1994 Jun 17;77(6):853–861. [PubMed]
  • Nussbaum RL, Airhart SD, Ledbetter DH. A rodent-human hybrid containing Xq24-qter translocated to a hamster chromosome expresses the Xq27 folate-sensitive fragile site. Am J Med Genet. 1986 Jan-Feb;23(1-2):457–466. [PubMed]
  • Woodford KJ, Howell RM, Usdin K. A novel K(+)-dependent DNA synthesis arrest site in a commonly occurring sequence motif in eukaryotes. J Biol Chem. 1994 Oct 28;269(43):27029–27035. [PubMed]
  • Kohwi Y, Kohwi-Shigematsu T. Magnesium ion-dependent triple-helix structure formed by homopurine-homopyrimidine sequences in supercoiled plasmid DNA. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3781–3785. [PMC free article] [PubMed]
  • Baran N, Lapidot A, Manor H. Formation of DNA triplexes accounts for arrests of DNA synthesis at d(TC)n and d(GA)n tracts. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):507–511. [PMC free article] [PubMed]
  • Sen D, Gilbert W. A sodium-potassium switch in the formation of four-stranded G4-DNA. Nature. 1990 Mar 29;344(6265):410–414. [PubMed]
  • Hardin CC, Corregan M, Brown BA, 2nd, Frederick LN. Cytosine-cytosine+ base pairing stabilizes DNA quadruplexes and cytosine methylation greatly enhances the effect. Biochemistry. 1993 Jun 8;32(22):5870–5880. [PubMed]
  • Aboul-ela F, Koh D, Tinoco I, Jr, Martin FH. Base-base mismatches. Thermodynamics of double helix formation for dCA3XA3G + dCT3YT3G (X, Y = A,C,G,T). Nucleic Acids Res. 1985 Jul 11;13(13):4811–4824. [PMC free article] [PubMed]
  • Sklenár V, Feigon J. Formation of a stable triplex from a single DNA strand. Nature. 1990 Jun 28;345(6278):836–838. [PubMed]
  • Fry M, Loeb LA. The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4950–4954. [PMC free article] [PubMed]
  • Hammond-Kosack MC, Kilpatrick MW, Docherty K. Analysis of DNA structure in the human insulin gene-linked polymorphic region in vivo. J Mol Endocrinol. 1992 Dec;9(3):221–225. [PubMed]
  • Liu Z, Gilbert W. The yeast KEM1 gene encodes a nuclease specific for G4 tetraplex DNA: implication of in vivo functions for this novel DNA structure. Cell. 1994 Jul 1;77(7):1083–1092. [PubMed]
  • Kunkel TA. DNA replication fidelity. J Biol Chem. 1992 Sep 15;267(26):18251–18254. [PubMed]
  • Mixon JC, Dev VG. Fragile X expression is decreased by 5-azacytidine and S-adenosylhomocysteine. Am J Hum Genet. 1983 Nov;35(6):1270–1275. [PMC free article] [PubMed]
  • McDermott A, Walters R, Howell RT, Gardner A. Fragile X chromosome: clinical and cytogenetic studies on cases from seven families. J Med Genet. 1983 Jun;20(3):169–178. [PMC free article] [PubMed]
  • Macpherson JN, Bullman H, Youings SA, Jacobs PA. Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation. Hum Mol Genet. 1994 Mar;3(3):399–405. [PubMed]

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